Cystic fibrosis (CF) is the most common life-shortening genetic disease in the white population. It occurs in the USA in about 1/3,300 white births, 1/15,300 black births, and 1/32,000 Asian-American births; 30% of patients are adults. See, e.g., Berkow (ed.) The Merck Manual of Diagnosis and Therapy Merck & Co., Rahway, N.J.; Thorn, et al. Harrison's Principles of Internal Medicine McGraw-Hill, N.Y.; and Weatherall, et al. (eds.) Oxford Textbook of Medicine Oxford University Press, Oxford; the Cystic Fibrosis Foundation website (www.cff.org); Davis (ed. 1993) Cystic Fibrosis Marcel Dekker, ISBN: 082478815X; Dodge (ed. 1996) Cystic Fibrosis: Current Topics Wiley & Son, ISBN: 0471963534; Bauernfeind, et al. (eds. 1996) Cystic Fibrosis Pulmonary Infections: Lessons from Around the World (Respiratory Pharmacology and Pharmacotherapy) Springer Verlag, ISBN: 081765027X; Orenstein and Stern (eds. 1998) Treatment of the Hospitalized Cystic Fibrosis Patient Marcel Dekker, ISBN: 0824795008; Hodson, et al. (eds. 2000) Cystic Fibrosis Oxford Univ. Press, ISBN: 0340742089; and Yankaskas and Knowles (eds. 1999) Cystic Fibrosis in Adults Lippincott Pubs, ISBN: 0781710111. See also Conese and Assael (2001) “Bacterial infections and inflammation in the lungs of cystic fibrosis patients” Ped. Infect. Dis. J. 20:207-213; Moss (2001) “New approaches to cystic fibrosis” Hosp. Pract. (Off. Ed.) 36:25-27, 31-32, 35-37; Robinson (2001) “Cystic fibrosis” Thorax 56:237-241; Ratjen (2001) “Changes in strategies for optimal antibacterial therapy in cystic fibrosis” Int. J. Antimicrob. Agents 17:93-96; Hodson (2000) “Treatment of cystic fibrosis in the adult” Respiration 67:595-607; Doring, et al. (2000) “Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus” Eur. Respir. J. 16:749-767; Beringer and Appleman (2000) “Unusual respiratory bacterial flora in cystic fibrosis: microbiologic and clinical features” Curr. Opin. Pulm. Med. 6:545-550; Larson and Cohen (2000) “Cystic fibrosis revisited” Mol. Genet. Metab. 71:470-477; Nasr (2000) “Cystic fibrosis in adolescents and young adults” Adolesc. Med. 11:589-603; Rahman and MacNee (2000) “Oxidative stress and regulation of glutathione in lung inflammation” Eur. Respir. J. 16:534-554; and Koch and Hoiby (2000) “Diagnosis and treatment of cystic fibrosis” Respiration 67:239-247.
CF is typically carried as an autosomal recessive trait by about 3% of the white population. The most common gene responsible has been localized to 250,000 base pairs of genomic DNA on chromosome 7q (the long arm). This encodes a membrane-associated protein called the cystic fibrosis transmembrane regulator (CFTR). The most common gene mutation, F508, leads to absence of a phenylalanine residue at position 508 on the CFTR protein and is found on about 70% of CF alleles; >600 less common mutations account for the remaining 30%. Although the exact function of CFTR is unknown, it appears to be part of a cAMP-regulated Cl− channel and appears to regulate Cl− and Na+ transport across epithelial membranes. Heterozygotes may show subtle abnormalities of epithelial transport but are clinically unaffected.
Fifty percent of affected patients present with pulmonary manifestations, usually chronic cough and wheezing associated with recurrent or chronic pulmonary infections. Cough is typically the most troublesome complaint, often accompanied by sputum, gagging, vomiting, and disturbed sleep. Intercostal retractions, use of accessory muscles of respiration, a barrel-chest deformity, digital clubbing, and cyanosis occur with disease progression. Upper respiratory tract involvement includes nasal polyposis and chronic or recurrent sinusitis. Adolescents may have retarded growth, delayed onset of puberty, and a declining tolerance for exercise. Pulmonary complications in adolescents and adults include pneumothorax, hemoptysis, and right heart failure secondary to pulmonary hypertension.
Cystic fibrosis still presents major health problems to afflicted individuals. It is a highly debilitating condition, and affects significant numbers of patients. As such, there is great need for new and more effective treatments. The present invention addresses these and other problems.